Chunk #2 — Endocannabinoid Variants and Childhood Adversity Predict Cannabis Dependence Symptoms and Amygdala Habituation — Challenges with A Priori Selection of Candidate Variants
Traditional candidate gene analyses, historically conducted in modestly sized samples of less than 500 participants, relied on a handful of genotypes selected for their purported functional effects on behavior. Reliance on such restricted sets of variants was primarily due to an oversimplification of genotype-phenotype relationships. For instance, if positive reinforcement is a core feature of substance use and is related to the release of dopamine, then variants associated with differential dopamine function (e.g., rs1800497 in DRD2/ANKK1) must be of importance to cannabis dependence (Maldonado & Rodriquez de Forseca, 2002). While the hypothesis that dopaminergic mechanisms, even specifically DRD2 receptors, are at play is fairly reasonable, a recent meta-analysis suggests no association between this polymorphism and cannabis dependence (Deng et al., 2015). Prior limitations with annotation of the human genome, compounded by the prohibitive costs associated with large-scale genotyping, likely relegated the implementation of early genetic association studies to a limited number of handpicked variants across genes and/or gene-tagging single nucleotide polymorphisms (SNPs). However, recent improvements in feasibility, customizability, and affordability of genome-wide arrays, the practicality of imputing, and the efficiency
